Epidemiology and Etiology of Primary Hyperparathyroidism

• PHPT is defined as:
  • Hypercalcemia or widely fluctuating serum calcium levels:
    • Resulting from the inappropriate or autogenous secretion of PTH by one or more parathyroid glands:
      • In the absence of a known or recognized stimulus
• The most common cause of hypercalcemia in the outpatient setting is PHPT:
  • With approximately 100,000 new cases per year reported in the United States
• Since the advent of routine laboratory testing, the prevalence of the disease has increased from:
  • 0.1% to 0.4%:
    • One to seven cases per 1000 adults
• In a study by Yeh et al:
  • The incidence of PHPT fluctuated between 36.3 and 120.2 cases per 100,000 women-years and 13.4 and 35.6 in 100,000 men-year
• PHPT may present at any age:
  • With the vast majority of cases occurring in patients:
    • Older than 45 years of age
• The mean age at diagnosis has remained between:
  • 52 and 56 years
• Women have consistently made up the preponderance of cases:
  • With a female-to-male ratio of 3:1 to 4:1
    • Based on a population based study from Rochester Minnesota the higher incidence of this could be:
      • Secondary (hypothetically) to estrogen deficiency after menopause:
        • That reveals underlying HPT
• The precise origin of PHPT is unknown:
  • Although exposure to:
    • Low-dose therapeutic ionizing radiation and familial predisposition account for some cases
  • Irradiation for acne could have accounted for a 2 to 3-fold increase in the incidence of this disease at some point in time, and a 4-fold increase was noted in survivors of the atomic bomb
  • Schneider et al:
    • In their study of 2555 patients followed for 50 years:
      • Even low doses of radiation exposure during the teenage years was associated with a slight risk of developing PHPT
    • In this study a dose response was documented in people receiving external- beam radiotherapy for benign diseases before their 16th birthday
    • The latency period for the development of PHPT after radiation exposure:
      • Is longer than that for the development of thyroid tumors:
        • With most cases occurring 30 to 40 years after exposure
    • Patients who have been radiated have similar clinical manifestations and serum calcium levels when compared to patients without a history of radiation exposure:
      • However, the former tend to have higher PTH levels and a higher incidence of concomitant thyroid neoplasms
• Certain medications have been implicated in the development of hypercalcemia:
  • Lithium therapy has been known to shift the set point for PTH secretion in parathyroid cells:
    • Thereby resulting in elevated PTH levels and mild hypercalcemia
    • The mechanism probably results from:
      • Lithium linking with the calcium sensing receptor on the parathyroid glands:
        • Resulting in PTH secretion
    • Lithium stimulates the growth of abnormal parathyroid glands in vitro and also in susceptible patients in vivo
    • Unusual metabolic features associated with lithium use include:
      • Low urinary calcium excretion
      • Normal cyclic AMP excretion
      • Lack of calcic nephrolithiasis
  • Elevated serum calcium levels have been associated with thiazide diuretic:
    • The overall annual age- and sex-adjusted (to 2000 U.S. whites) incidence was:
      • 7.7 (95% CI, 5.9 to 9.5) per 100,000 individuals
    • The average 24-hour plasma calcium concentrations are:
      • Increased with thiazide diuretic use:
        • But the mean 24-hour PTH levels remain unchanged:
          • In subjects with normal baseline PTH levels and no evidence of hypercalciuria
    • Thiazides diuretics have several metabolic effects that may contribute to increased calcium levels:
      • A decrease in urine calcium excretion is the most likely cause:
        • But in some cases diuretic use has been associates with a metabolic alkalosis:
          • That could also cause an increase in total serum calcium levels:
            • Through a pH-dependent increase in protein-bound calcium
      • Although plasma 1,25 (OH) vitamin D levels are unchanged:
        • Increased intestinal calcium absorption in response to thiazide diurectic use:
          • Has been noted and could also contribute to an increase in serum calcium
        • One last possible explanation for the elevated serum calcium levels associated with thiazide diuretic use is:
          • Hemoconcentration associated with dieresis
• Numerous genetic abnormalities have been identified in the development of PHPT, including:
  • Anomalies in tumor suppressor genes and proto-oncogenes
  • Specific DNA mutations in a parathyroid cell may confer a proliferative advantage over normal neighboring cells:
    • Thus allowing for clonal growth:
      • Large populations of these altered cells containing the same mutation within hyper functioning parathyroid tissue suggest that such glands are a result of clonal expansion
• The majority of PHPT cases are:
  • Sporadic
• Nonetheless, PHPT also occurs within the spectrum of a number of inherited disorders such as:
  • Multiple endocrine neoplasia syndromes (MEN):
    • MEN type 1 (Wermer Syndrome)
    • MEN type 2A (Sipple Syndrome)
    • Isolated familial HPT
    • Familial HPT with jaw-tumor syndrome
      • All of these syndromes are inherited in an:
        • Autosomal dominant fashion
• The earliest and most common presentation of MEN1 is:
  • PHPT:
    • It develops in approximately 80% to 100% of patients by age 40 years
  • These patients also are predisposed to the development of:
    • Pancreatic neuroendocrine tumors
    • Pituitary adenomas
    • Less frequently to:
      • Skin angiomas
      • Lipomas
      • Adrenocortical tumors
      • Neuroendocrine tumors of the thymus, bronchus, or stomach
  • MEN type 1 has been shown to result from a germline mutation:
    • In a tumor suppressor gene:
      • Called MEN1 gene:
        • Located on chromosome 11q12-13
      • It encodes Menin:
        • A protein that is postulated to interact with:
          • The transcription factors JunD and nuclear factor-κB in the nucleus
          • In addition to replication protein A and other proteins
    • Pre-symptomatic screening for mutation carriers for MEN type 1:
      • Is difficult because generally MEN1 mutations result in a nonfunctional protein and are scattered throughout the translated nine exons of the gene
    • MEN1 mutations also have been found in kindred’s initially suspected to represent isolated familial HPT
    • Screening for mutation carriers for MEN type 1:
      • Has a very high detection rate:
        • Greater than 94%
      • It is used in Sweden for patients with PHPT with:
        • A first-degree relative with a major endocrine tumor
        • Age of onset is less than 30 years
        • Multiple pancreatic tumors /parathyroid hyperplasia is detected
          • Thus these patients should be screened for MEN1 mutations
• Approximately 20% of patients with MEN type 2A (Sipple Syndrome) develop PHPT which is usually less severe:
  • MEN type 2A is caused by a:
    • Germline mutation of the:
      • RET proto-oncogene located on chromosome 10
  • Genotype and phenotype correlations have been noted in this syndrome:
    • In that individuals with mutations at codon 634:
      • Are more likely to develop PHPT
• Patients with the familial HPT with jaw-tumor syndrome have an increased predisposition to parathyroid carcinoma:
  • This syndrome maps to a:
    • Tumor suppressor locus HRPT2 (parafibromin) on chromosome 1
• Sporadic parathyroid adenomas and some hyperplastic parathyroid glands have:
  • Loss of heterozygosity (LOH) at 11q13:
    • The site of the MEN1 gene:
      • In approximately 25% to 40% of the cases
• Over expression of PRAD1:
  • Which encodes cyclin D1:
    • A cell cycle control protein:
      • Is found approximately 18% of parathyroid adenomas:
        • This was proven to result from a rearrangement on chromosome 11 that places the PRAD1 gene under the control of the PTH promoter
• Other chromosomal regions deleted in parathyroid adenomas and possibly reflecting loss of tumor suppressor genes include:
  • 1p, 6q, and 15q
• Whereas amplified regions suggesting on co genes have been identified at 16p and 19p
• RET mutations are unusual in sporadic parathyroid tumors
• Sporadic parathyroid cancers are characterized by uniform loss of the tumor suppressor gene RB:
  • Which is involved in cell cycle regulation:
    • 60% have HRPT2 (CDC73) mutations
• These alterations are rare in benign parathyroid tumors and may have implications for diagnosis
• The p53 tumor suppressor gene:
  • Is also inactivated in a subset (30%) of parathyroid carcinomas
• Single gland adenoma is the most common cause of PHPT:
  • 75% to 85% of the cases
• Lower pole adenomas (in relation to the thyroid):
  • Are more common than are upper pole adenomas
• Sizes range from:
  • 1 cm to 3 cm
• The normal weight of a parathyroid gland is approximately 40 to 50 mg:
  • The weight of parathyroid adenomas vary between 553.7 +/- 520.5 mg (range, 66-2536)
• Ectopic glands can be present:
  • 4% to 16% of cases
• PHPT is caused by:
  • The enlargement of a single parathyroid gland or parathyroid adenoma in approximately:
    • 75% to 89% of the cases
  • Multiple adenomas or hyperplasia in 15% to 25% of the cases
  • Parathyroid carcinoma as the cause of PHPT is:
    • Extremely rare in most parts of the world (~1%) of patients
  • Multi-gland adenoma arises in a significant number of patients:
    • Double adenomas are seen in approximately 2% to 12% of the cases,
    • Triple adenomas in less than 1% the cases
    • Four adenomas or parathyroid gland hyperplasia in less than 3% to 15% of the cases
• Most parathyroid adenomas consist of parathyroid chief cell:
  • They are usually encapsulated and in 50% of the cases they are surrounded by normal parathyroid tissue
• Some adenomas, nevertheless, are composed of oxyphil cells:
  • These adenomas are usually larger than chief cell adenomas
• Parathyroid adenomas are sometimes located within the thymus and they express a parathyroid-specific gene, GCMB:
  • Contrasting with the normal thymus:
    • Which does not express neither PTH nor GCMB
• In a study by Ruda et al:
  • 20, 225 patients with PHPT:
    • Parathyroid hyperplasia accounted for approximately 6% of cases
    • In parathyroid hyperplasia all four glands are enlarged:
      • With the lower glands typically being larger than the upper ones
    • The glands are usually composed of chief cells
    • Clear cell hyperplasia is very rare, and is the only form in which the upper glands are larger than the lower ones

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